1. Field of the Invention
The present invention relates to pharmaceuticially active compounds, including certain substituted indolinyl (and derivatives thereof), 1,2,3,4-tetrahydroquinolinyl (and derivatives thereof), 1,2,3,4-tetrahydroisoquinolinyl, benz[cd]indolinyl and 5,6-dihydrophenanthridinyl compounds, and methods of treatment and pharmaceutical compositions that utilize or comprise one or more such compounds. Compounds of the invention are particularly useful for the treatment or prophylaxis of neurological injury and neurodegenerative disorders.
2. Background
Nerve cell death (degeneration) can cause potentially devastating and irreversible effects for an individual and may occur e.g. as a result of stroke, heart attack or other brain or spinal chord ischemia or trauma. Additionally. neurodegenerative disorders involve nerve cell death (degeneration) such as Alzheimer""s disease, Parkinson""s disease, Huntington""s disease, Amyotrophic Lateral Sclerosis, Down""s Syndrome and Korsakoffs disease.
Therapies have been investigated to treat nerve cell degeneration and related disorders, e.g., by limiting the extent of nerve cell death that may otherwise occur to an individual. See, e.g., N. L. Reddy et al., J. Med. Chem., 37:260-267 (1994); and WO 95/20950.
The compound MK-801 has exhibited good results in a variety of in vivo models of stroke. See B. Meldrum, Cerbrovascular Brain Metab. Rev., 2:27-57 (1990): D. Choi, Cerbrovascular Brain Metab. Rev., 2:105-147 (1990). See also Merck Index, monograph 3392, 11th ed., 1989. For example, MK-801 exhibits good activity in mouse audiogenic tests, a recognized model for evaluation of neuroprotective drugs. See, e.g.. M. Tricklebank et al., European Journal of Pharmacology, 167:127-135 (1989); T. Seyfried, Federation Proceedings, 38(10):2399-2404 (1979).
However, MK-801 also has shown toxicity and further clinical development of the compound is currently uncertain. See J. W. Olney et al., Science, 244:1360-1362 (1989); W. Koek et al., J. Pharmacol. Exp. Ther., 252:349-357 (1990); F. R. Sharp et al., Society for Neuroscience Abstr., abstr. no. 482.3 (1992).
It thus would be highly desirable to have new neuroprotective agents, particularly agents to limit the extent or otherwise treat nerve cell death (degeneration) such as may occur with stroke, heart attack or brain or spinal cord trauma, or to treat neurodegenerative disorders such as Alzheimer""s disease, Parkinson""s disease, Huntington""s disease, Amyotrophic Lateral Sclerosis, Down""s Syndrome and Korsakoff""s disease.
In a first aspect, the present invention provides substituted indolinyl and indolinyl derivative compounds of the following Formula I: 
wherein
R and R1 are each independently hydrogen; substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms; substituted or unsubstituted akynyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms; substituted or unsubstituted aninoalkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfinyl having 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfonyl having 1 to about 20 carbon atoms; substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms; or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms, with at least one of R and R1 being other than hydrogen;
each R2 and each R3 (i.e. substituent of the 4, 5, 6 and 7 aromatic ring positions) are each independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms, or substituted or unsubstituted aralkyl having at least about 6 ring carbon atoms;
X is substituted or unsubstituted methylene (xe2x80x94CH2xe2x80x94), xe2x80x94Sxe2x80x94 (i.e. 3-benzothiazolinylcarboximidamide compounds), xe2x80x94Oxe2x80x94 or substituted or unsubstituted xe2x80x94Nxe2x80x94, and preferably is substituted or unsubstituted methylene;
m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
In a further aspect, the invention provides compounds of the following Formula II: 
wherein
R and R1 are each independently hydrogen; substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms; substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfinyl having 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfonyl having 1 to about 20 carbon atoms; substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms; or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms;
each R2 (i.e. substituent of the 2 and 3 ring positions) and each R3 (i.e. substituent of the 5, 6, 7 and 8 aromatic ring positions) are each independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms, or substituted or unsubstituted aralkyl having at least about 6 ring carbon atoms;
X is xe2x80x94Oxe2x80x94 (i.e. 2,3-benzmorpholinyl compounds), xe2x80x94Sxe2x80x94 (i.e. 2,3-benzthiomorpholinyl compounds), substituted or unsubstituted xe2x80x94Nxe2x80x94, or substituted or unsubstituted methylene (xe2x80x94CH2xe2x80x94);
m and n are each independently 0 (i.e. the available ring are each hydrogen-substituted), 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
In a still further aspect, the invention provides tetrahydroisoquinolinyl compounds of the following Formula III: 
wherein
R and R1 are each independently hydrogen; substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms; substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfinyl having 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfinyl having 1 to about 20 carbon atoms; substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms; or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms;
each R2 (i.e. substituent of the 1, 3 and 4 tetrahydroisoquinolinyl ring positions) and each R3 (i.e. substituent of the 5, 6, 7 and 8 tetrahydroisoquinolinyl ring positions) are each independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms, or substituted or unsubstituted aralkyl having at least about 6 ring carbon atoms;
m is 0 (i.e. the 1, 3 and 4 tetrahydroisoquinolinyl ring positions are each hydrogen-substituted), 1, 2, 3, 4, 5 or 6; n is 0 (i.e. the 5, 6, 7 and 8 tetrahydroisoquinolinyl ring positions are each hydrogen-substituted), 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
In a yet further aspect, the invention provides compounds of the following Formula IV: 
wherein
R and R1 are each independently hydrogen; substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms; substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfinyl having 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfonyl having 1 to about 20 carbon atoms; substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms; or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms, with at least one of R and R1 being other than hydrogen;
each R2 and each R3 (i.e. substituent of the aromatic positions 3-8) are each independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms, or substituted or unsubstituted aralkyl having at least about 6 ring carbon atoms;
m is 0 (i.e. the 2-benz[cd]indolinyl position is hydrogen-substituted), 1 or 2; and n is 0 (i.e. the available ring are each hydrogen-substituted), 1, 2, 3, 4, 5 or 6; and pharmaceutically acceptable salts thereof.
Still further, the invention provides compounds of the following Formula V: 
wherein
R and R1 are each independently hydrogen; substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms; substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylthio having from 1 to about 20 carbon atoms; substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfinyl having 1 to about 20 carbon atoms; substituted or unsubstituted alkylsulfonyl having 1 to about 20 carbon atoms; substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms; or a substituted or unsubstituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms, with at least one of R and R1 being other than hydrogen;
each R2, each R3 (i.e. substituent of the aromatic positions 1-4) and each R4 (i.e. substituent of the aromatic positions 7-10) are each independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkenyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkynyl having from 2 to about 20 carbon atoms, substituted or unsubstituted alkoxy having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylthio having 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms, substituted or unsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkyl having from 1 to about 20 carbon atoms, substituted or unsubstituted carbocyclic aryl having at least about 6 ring carbon atoms, or substituted or unsubstituted aralkyl having at least about 6 ring carbon atoms;
m is 0 (i.e. the 5,6-dihydrophenanthridinyl ring position is hydrogen-substituted), 1 or 2; and n and r are each independently 0 (i.e. the ring positions are each hydrogen-substituted), 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
In a yet further aspect the invention provides compounds of the following Formulae VI: 
wherein R, R1, X, R2, R3 and n are the same as defined above for Formula II, but where X can also be sulfinyl (i.e. xe2x80x94S(O)xe2x80x94) or sulfonyl (i.e. xe2x80x94S(O2)xe2x80x94), and m of Formula VI is an integer equal to 0-6, and preferably m is 0, 1 or 2; and pharmaceutically acceptable salts thereof. Preferred substituents of Formula II also will be preferred substituents at corresponding positions of compounds of of Formula VI.
The invention also provides compounds of the following Formula VII: 
wherein R, R1, R2, R3 and m are the same as defined above for Formula IV, and n of Formula VII is an integer equal to 0-9, and preferably n is 0, 1 or 2; and pharmaceutically acceptable salts thereof. It is understood that an R3 substituent can be the same or different and may be present on either the non-aromatic or aromatic fused ring. Preferred substituents of Formula IV also will be preferred substituents at corresponding positions of compounds of Formula VI.
The invention also provides compounds of the following Formula VIII: 
wherein R, R1, R2, R3, n and r are the same as defined above for Formula V, except R and R1 each may be hydrogen, although preferably at least one of R and R1 will be other than hydrogen, and m of Formula VIII is an integer equal to 0-4, and preferably m is 0, 1 or 2, and the dotted line in Formula VIII represents an optional carbon-carbon double bond (endocyclic bond); and pharmaceutically acceptable salts thereof. Preferred substituents of Formula V also will be preferred substituents at corresponding positions of compounds of Formula VIII.
The invention also provides compounds of the following Formula IX: 
wherein R2, R3, n and r are the same as defined above for Formula V; R and R1 are also the same as defined above for Formula V, except R and R1 each may be hydrogen, although preferably at least one of R and R1 will be other than hydrogen; m of Formula IX is an integer equal to 0-6 (i.e. R2 may be a substituent at any of the available three saturated ring positions), and preferably m is 0, 1 or 2.
For each of Formulae I, II, III, IV and V, as well as for each of Formulae VI, VII, VII and IX and Formulae Ixe2x80x3 and IIxe2x80x3 as defined below, preferably at least one of R and R1 is a carbocyclic aryl, aralkyl, or heteroaromatic or heteroalicyclic group, particularly substituted or unsubstituted phenyl or naphthyl. More preferably, for each of Formulae I through IX (which includes Formulae Ixe2x80x3 and IIxe2x80x3), R is a carbocyclic aryl, heteroaromatic or heteroalicyclic group, and R1 is a non-aryl group, particularly hydrogen or substituted or unsubstituted alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, or aminoalkyl. Substituted or unsubstituted phenyl or naphthyl are preferred R groups of Formulae 1 through IX (including Formulae Ixe2x80x3 and IIxe2x80x3). Generally more preferred R1 groups are hydrogen and substituted or unsubstituted alkyl such as substituted or unsubstituted alkyl having 1 to about 6 carbon atoms or 1 to about 3 carbon atoms.
The compounds of the invention (i.e. compounds of Formulae I, II, III, IV and V as well as compounds of Formulae Ixe2x80x2, Ixe2x80x3, Ia, Iaa, Ib, IIxe2x80x3, IIa, IIaa, IIb, IIIa, IIIaa, IIIb, IVa, IVaa, IVb, Va, Vaa and Vb as discussed below, and as well as compounds of Formulae VI, VII, VIII and IX above) are useful for a number of therapeutic applications. In particular, the invention includes methods for treatment and/or prophylaxis of neurological conditions/injuries such as epilepsy, neurodegenerative conditions and/or nerve cell death (degeneration) resulting from e.g. hypoxia, hypoglycemia, brain or spinal chord ischemia, retinal ischemia, brain or spinal chord trauma or post-surgical neurological deficits and the like as well as neuropathic pain. The compounds of the invention are especially useful for treatment of a person susceptible or suffering from stroke or heart attack or neurological deficits relating to cardiac arrest, a person suffering or susceptible to brain or spinal cord injury, or a person suffering from the effects of retinal ischemica or degeneration, or a person suffering from decreased blood flow or nutrient supply to retinal tissue or optic nerve or retinal trauma or optic nerve injury. Compounds of the invention also are useful to treat and/or prevent various neurodegenerative diseases such as Parkinson""s disease, Huntington""s disease, Amyotrophic Lateral Sclerosis, Alzheimer""s disease, Down""s Syndrome, Korsakoff""s disease, cerebral palsy and/or age-dependent dementia. Compounds of the invention will be further useful to treat and/or prevent migraines, shingles (herpes zoster), epilepsy, emesis and/or narcotic withdrawal symptoms. The treatment methods of the invention in general comprise administration of a therapeutically effective amount of one or more compounds of the invention to an animal, including a mammal, particularly a human.
Particularly preferred compounds of the invention exhibit good activity in an anticonvulsant in vivo mouse audiogenic assay e.g. as disclosed in Example 48 which follows, preferably about 20% or more inhibition at a dose of a compound of the invention of 20 mg/kg, more preferably about 50% or more or 70% or more inhibition at a dose of 20 mg/kg in such an anticonvulsant in vivo audiogenic assay.
The invention also provides pharmaceutical compositions that comprise one or more compounds of the invention and a suitable carrier for the compositions.
Other aspects of the invention are disclosed infra.
As mentioned above, preferred compounds of Formula I include those where the group X is substituted or unsubstituted methylene, i.e. indolinyl compounds of the following Formula Ixe2x80x2: 
where R, R1, R2, R3 and n are each the same as defined above for Formula I, m is 0, 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
Preferred compounds of Formula I as defined above include those where R is substituted or unsubstituted carbocyclic aryl, particularly substituted or unsubstituted phenyl, naphthyl and acenaphthyl.
Substituted and unsubstituted phenyl and naphthyl are particularly preferred R group of compounds of Formula I, such as compounds of the following Formulae Ia and Iaa: 
wherein for each of Formulae Ia and Iaa
each Rxe2x80x3 is independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alknyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, or substituted or unsubstituted aralkyl;
p is an integer of 0 (where the phenyl ring is fully hydrogen substituted), 1, 2, 3, 4 or 5, and more preferably is 1, 2 or 3;
s is an integer of from 0 to 7, and more preferably is 0 (where the naphthyl ring is fully hydrogen-substituted), 1, 2, 3 or 4;
R1, R2, R3, X, m and n are each the same as defined above for Formula I; and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of Formula Ia include those where p is 1 or greater, e.g. compounds that are substituted at the ortho, meta and/or para phenyl ring positions by Rxe2x80x3 group(s) other than hydrogen, or 2,5-phenyl ring substituted, 2,3,5-phenyl ring substituted or 2,4,5-phenyl ring substituted by Rxe2x80x3 groups other than hydrogen(s) such as halogen, substituted or unsubstituted alkyl having 1 to about 6 carbon atoms, substituted or unsubstituted alkoxy having 1 to about 6 carbon atoms, or substituted or unsubstituted alkylthio having 1 to about 6 carbon atoms. It is of course understood that where a phenyl or napthyl group of Formulae Ia or Iaa is not substituted by an Rxe2x80x3 group, the ring position is hydrogen-substituted. While as shown by the above structure Formula Iaa includes compounds that have either a 1-naphthyl or 2-naphthyl amino (xe2x80x94N(R1)xe2x80x94) substituent, compounds having a 1-naphthyl group are generally more preferred. Compounds of Formula Iaa that have a non-hydrogen Rxe2x80x3 substituent at the 4-naphthyl position are also particularly preferred.
Compounds of Formula I may suitably contain one or more indolinyl (or derivative) ring substituents, i.e. the sum of the values of m and n of Formula I is one or more. It is understood that references herein to xe2x80x9cderivativesxe2x80x9d of indolinyl compounds of Formula I refer to those compounds where the group X is other than substituted or unsubstituted methylene.
Generally preferred compounds of Formula I that include indolinyl (or derivative) substituents contain no more than one or two non-hydrogen R2 substituents, such as compounds that contain 0 (i.e. ring position 2 is xe2x80x94CH2xe2x80x94) or 1 (i.e. ring position 2 is xe2x80x94CH2xe2x80x94) non-hydrogen R2 substituents. Similarly, generally referred compounds of Formula Ixe2x80x2 that include indolinyl ring substitutents contain no more than two or three non-hydrogen R2 substitutents, such as compounds that contain 0 (i.e. each of ring positions 2 and 3 is xe2x80x94CH2xe2x80x94) or 1 (i.e. one indolinyl ring position is xe2x80x94CH2xe2x80x94 and the other is xe2x80x94CH(R2)xe2x80x94) non-hydrogen R2 substituents.
Generally preferred compounds of Formula I also include those that contain 0 (ring, positions 4-7 each hydrogen substituted), and 1 or 2 R3 ring substituents.
Preferred compounds of Formula I also include those compounds that are unsubstituted on the ring (each m and n as defined above for Formula I is 0), i.e. compounds of the following Formula Ib: 
wherein the groups R, R1 and X are the same as defined above for Formula I; and pharmaceutically salts thereof. The above noted preferred R and R1 groups of Formula I are also preferred groups of compounds of Formula Ib.
In another aspect, compounds of Formula Ixe2x80x3 are provided, which is defined the same as Formula I above, but where X is sulfinyl (i.e. xe2x80x94S(O)xe2x80x94) or sulfonyl (i.e. xe2x80x94S(O2xe2x80x94). Preferred substitutents of compounds of Formula I as noted herein are also preferred substituents for corresponding positions for compounds of Formula Ixe2x80x3.
Preferred compounds of Formula II include those where R is substituted or unsubstituted carbocyclic aryl such as substituted or unsubstituted phenyl, naphthyl or acenaphthyl, particularly substituted or unsubstituted phenyl or naphthyl, i.e. compounds of the following Formulae IIa and IIaa: 
wherein for each of Formulae Ia and IIaa
each Rxe2x80x3 is independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, or substituted or unsubstituted aralkyl;
p is an integer of 0 (where the phenyl ring is fully hydrogen substituted), 1, 2, 3, 4 or 5, and more preferably is 1, 2 or 3;
s is an integer of from 0 to 7, and more preferably is 0 (i.e. where the naphthyl ring is fully hydrogen-substituted), 1, 2, 3 or 4;
R1, R2, R3, X, m and n are each the same as defined above for Formula II; and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of Formula IIa include those where p is 1 or greater, e.g. compounds that are substituted at the ortho, meta and/or para phenyl ring positions by Rxe2x80x3 group(s) other than hydrogen, or 2,5-phenyl ring substituted, 2,3,5-phenyl ring substituted or 2,4,5-phenyl ring substituted by non-hydrogen Rxe2x80x3 groups such as halogen, substituted or unsubstituted alkyl having 1 to about 6 carbon atoms, substituted or unsubstituted alkoxy having 1 to about 6 carbon atoms, or substituted or unsubstituted alkylthio having 1 to about 6 carbon atoms. It is of course understood that where a phenyl or napthyl group of Formulae IIa or IIaa is not substituted by an Rxe2x80x3 group, the ring position is hydrogen-substituted. While as shown by the above structure Formula IIaa includes compounds that have either a 1-naphthyl or 2-naphthyl amino (xe2x80x94N(R1)xe2x80x94) substituent, compounds having a 1-naphthyl group are generally more preferred. Compounds of Formula IIaa that have a non-hydrogen Rxe2x80x3 substituent at the 4-naphthyl position are also particularly preferred.
Compounds of Formula II may suitably contain one or more tetrahydroquinolinyl (or derivative thereof) ring substituents, i.e. the sum of the values of m and n of Formula II is one or more. It is understood that references herein to xe2x80x9cderivativesxe2x80x9d of tetrahydroquinolinyl compounds of Formula II refer to those compounds where the group X is other than substituted or unsubstituted methylene.
Generally preferred compounds of Formula II that include tetrahydroquinolinyl (or derivative thereof) ring substituents contain no more than about three non-hydrogen R2 substituents, including compounds that contain 0 (i.e. each of tetrahydroquinolinyl ring positions 2, 3 and 4 is xe2x80x94CH2xe2x80x94) or 1 (i.e. two ring positions is xe2x80x94CH2xe2x80x94 and the other is xe2x80x94CH(R2)xe2x80x94) R2 substituents. Generally preferred compounds also include those that contain 0 (ring positions 5-8 each hydrogen substituted), 1 or 2 non-hydrogen R3 ring substituents.
Preferred compounds of Formula II also include those that are unsubstituted on the tetrahydroquinolinyl (or derivative thereof) ring, i.e. m and n or Formula II are each 0, particularly compounds of the following Formula IIb: 
where R and R1 are the same as defined above for Formula II; and pharmaceutically acceptable salts thereof. The above noted preferred R and R1 groups of Formula II are also preferred groups of compounds of Formula IIb.
In another aspect, compounds of Formula IIxe2x80x3 are provided, which is defined the same as Formula II above. but where X is sulfinyl (i.e. xe2x80x94S(O)xe2x80x94) or sulfonyl (i.e. xe2x80x94S(O2)xe2x80x94). Preferred substitutents of compounds of Formula II as noted herein are also preferred substituents for corresponding positions for compounds of Formula IIxe2x80x3.
Preferred compounds of Formula III include those where R is substituted or unsubstituted carbocyclic aryl such as substituted or unsubstituted phenyl, naphthyl or acenaphthyl, particularly substituted or unsubstituted phenyl or naphthyl, i.e. compounds of the following Formulae IIIa and IIIaa: 
wherein for each of Formulae IIIa and IIIaa
each Rxe2x80x3 is independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, or substituted or unsubstituted aralkyl;
p is an integer of 0 (where the phenyl ring is fully hydrogen substituted), 1, 2, 3, 4 or 5, and more preferably is 1, 2 or 3;
s is an integer of from 0 to 7, and more preferably is 0 (i.e. where the naphthyl ring is fully hydrogen-substituted), 1, 2, 3 or 4;
R1, R2, R3, m and n are each the same as defined above for Formula III; and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of Formula IIIa include those where p is 1 or greater, e.g. compounds that are substituted at the ortho, meta and/or para phenyl ring positions by Rxe2x80x3 group(s) other than hydrogen, or 2,5-phenyl ring substituted, 2,3,5-phenyl ring substituted or 2,4,5-phenyl ring substituted by non-hydrogen Rxe2x80x3 groups such as halogen, substituted or unsubstituted alkyl having 1 to about 6 carbon atoms, substituted or unsubstituted alkoxy having 1 to about 6 carbon atoms, or substituted or unsubstituted alkylthio having 1 to about 6 carbon atoms. It is of course understood that where a phenyl or napthyl group of Formulae IIIa or IIIaa is not substituted by an Rxe2x80x3 group, the ring position is hydrogen-substituted. While as shown by the above structure Formula IIIaa includes compounds that have either a 1-naphthyl or 2-naphthyl amino (xe2x80x94N(R1)xe2x80x94) substituent, compounds having a 1-naphthyl group are generally more preferred. Compounds of Formula IIIaa that have a non-hydrogen Rxe2x80x3 substituent at the 4-naphthyl position are also particularly preferred.
Compounds of Formula III may suitably contain one or more tetrahydroisoquinolinyl ring substituents, i.e. the sum of the, values of m and n of Formula III is one or more.
Generally preferred compounds of Formula III that include tetrahydroisoquinolinyl ring substituents contain no more than about three non-hydrogen R2 substituents, including compounds that contain 0 (i.e. each of tetrahydroisoquinolinyl ring positions 1, 3 and 4 is xe2x80x94CH2xe2x80x94) or 1 (i.e. two ring positions are xe2x80x94CH2xe2x80x94 and the other is xe2x80x94CH(R2)xe2x80x94) non-hydrogen R2 substituents. Generally preferred compounds also include those that contain 0 (ring positions 5-8 each hydrogen substituted), 1 or 2 non-hydrogen R3 ring substituents.
Preferred compounds of Formula III also include those that are unsubstituted on the tetrahydroisoquinolinyl ring, i.e. m and n or Formula III are each 0, particularly compounds of the following Formula IIIb: 
where R and R1 are the same as defined above for Formula II; and pharmaceutically acceptable salts thereof. The above noted preferred R and R1 groups of Formula III are also preferred groups of compounds of Formula IIIb.
Preferred compounds of Formula IV as defined above include those where R is substituted or unsubstituted carbocyclic aryl, particularly substituted or unsubstituted phenyl, naphthyl and acenaphthyl.
Substituted and unsubstituted phenyl and naphthyl are particularly preferred R groups of compounds of Formula IV, such as compounds of the following Formulae IVa and IVaa: 
wherein for each of Formulae IVa and IVaa
each Rxe2x80x3 is independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, or substituted or unsubstituted aralkyl;
p is an integer of 0 (where the phenyl ring is fully hydrogen substituted), 1, 2, 3, 4 or 5, and more preferably is 1, 2 or 3;
s is an integer of from 0 to 7, and more preferably is 0 (i.e. where the naphthyl ring is fully hydrogen-substituted), 1, 2, 3 or 4;
R1, R2, R3, m and n are each as defined above for Formula IV; and pharmaceutically acceptable salts thereof.
Preferred compounds of Formula IVa include those where p is 1 or greater, e.g. compounds that are substituted at the ortho, meta and/or para phenyl ring positions by Rxe2x80x3 group(s) other than hydrogen, or 2,5-phenyl ring substituted, 2,3,5-phenyl ring substituted or 2,4,5-phenyl ring substituted by non-hydrogen Rxe2x80x3 groups such as halogen, substituted or unsubstituted alkyl having 1 to about 6 carbon atoms, substituted or unsubstituted alkoxy having 1 to about 6 carbon atoms, or substituted or unsubstituted alkylthio having 1 to about 6 carbon atoms. It is of course understood that where a phenyl or napthyl group of Formulae IVa or IVaa is not substituted by an Rxe2x80x3 group, the ring position is hydrogen-substituted. While as shown by the above structure Formula IVaa includes compounds that have either a 1-naphthyl or 2-naphthyl amino substituent, compounds having a 1-naphthyl group are generally more preferred. Compounds of Formula IVaa that have a non-hydrogen Rxe2x80x3 substituent at the 4-naphthyl position are also particularly preferred.
Compounds of Formula IV may suitably contain one or more benzindolinyl ring, substituents, i.e. the sum of the values of m and n of Formula IV is one or more.
Generally preferred compounds of Formula IV that include benzindolinyl ring substituents contain 0 R2 substituents (i.e. the 2 benz[cd]indolinyl positions is xe2x80x94CH2xe2x80x94), or 1 non-hydrogen R2 substituent.
Generally preferred compounds of Formula IV also include those that contain 0 (i.e. benz[cd]indolinyl ring positions 3-8 each hydrogen substituted), 1 or 2 R3 ring substituents.
Preferred compounds of Formula IV also include those compounds that are unsubstituted on the benzindolinyl ring (each m and n as defined above for Formula IV is 0), i.e. compounds of the following Formula IVb: 
wherein the groups R and R1 are the same as defined above for Formula III; and pharmaceutically salts thereof. The above noted preferred R and R1 groups of Formula IV are also preferred R and R1 groups of compounds of Formula IVb.
Preferred compounds of Formula V include those where R is substituted or unsubstituted carbocyclic aryl such as substituted or unsubstituted phenyl, naphthyl or acenaphthyl, particularly substituted or unsubstituted phenyl or naphthyl, such as compounds of the following Formulae Va and Vaa: 
wherein for each of Formulae Va and Vaa
each Rxe2x80x3 is independently hydrogen, halogen, hydroxyl, azido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl, or substituted or unsubstituted aralkyl;
p is an integer of 0 (where the phenyl ring is fully hydrogen substituted), 1, 2, 3, 4 or 5, and more preferably is 1, 2 or 3;
s is an integer from 0 to 7, and more preferably is 0 (i.e. where the naphthyl ring is fully hydrogen-substituted), 1, 2, 3 or 4;
R1, R2, R3, R4, m, n and r are each as defined above for Formula V; and pharmaceutically acceptable salts thereof.
Preferred compounds of Formula Va include those where p is 1 or greater, e.g. compounds that are substituted at the ortho and/or meta phenyl ring positions by Rxe2x80x3 groups other than hydrogen, or 2,5-phenyl ring substituted, 2,3,5-phenyl ring substituted or 2,4,5-phenyl ring substituted by Rxe2x80x3 groups other than hydrogen such as halogen, substituted or unsubstituted alkyl having 1 to about 6 carbon atoms, substituted or unsubstituted alkoxy having 1 to about 6 carbon atoms, or substituted or unsubstituted alkylthio. It is of course understood that where a phenyl or napthyl group of Formulae Va or Vaa is not substituted by an Rxe2x80x3 group, the ring position is hydrogen-substituted. While as shown by the above structure Formula Vaa includes compounds that have either a 1-naphthyl or 2-naphthyl amino substituent, compounds having a 1-naphthyl group are generally more preferred. Compounds of Formula Vaa that have a non-hydrogen Rxe2x80x3 substituent at the 4-naphthyl position are also particularly preferred.
Compounds of Formula V may suitably contain one or more 5,6-dihydrophenanthridinyl ring substituents. i.e. the sum of the values of m and n of Formula V is one or more.
Generally preferred compounds of Formula V include those compounds that contain 0 (i.e. the 6-hydrophenanthridinyl ring position is xe2x80x94CH2xe2x80x94), or 1 (i.e. the 6-hydrophenanthridinyl ring position is xe2x80x94CH(R2)xe2x80x94) non-hydrogen R2 substituents. Generally preferred compounds also include those that contain 0 (ring positions 5-8 each hydrogen substituted), 1 or 2 R3 and/or R4 ring substituents.
Preferred compounds of Formula V include those that are unsubstituted on the 5,6-dihydrophenanthridinyl ring (m, n and r each zero), particularly compounds of the following Formula Vb: 
where R and R1 are each the same as defined above for Formula V; and pharmaceutically acceptable salts thereof. The above noted preferred R and R1 groups of Formula V are also preferred R and R1 groups of compounds of Formula Vb.
Suitable halogen substituent groups of compounds of Formulae I, Ixe2x80x2, Ixe2x80x3, Ia, Iaa, Ib, II, IIxe2x80x3, IIa, IIaa, IIb, III, IIIa, IIIaa, IIIb, IV, IVa, IVaa, IVb, V, Va, Vaa, Vb, VI, VII, VIII or IX, as defined above (i.e. compounds of the invention) include F, Cl, Br and I. Alkyl groups of compounds Formulae I, Ixe2x80x3, II, IIxe2x80x3, III, IV, V, VI, VII, VIII or IX preferably have from 1 to about 12 carbon atoms. more preferably 1 to about 8 carbon atoms, still more preferably 1 to about 6 carbon atoms, even more preferably 1, 2, 3 or 4 carbon atoms. (It is understood that references herein to Formulae I; Ixe2x80x3; II; IIxe2x80x3; III; IV; and V apply equally to compounds of Formulae Ixe2x80x2, Ia, Iaa and Ib; IIa, IIaa and IIb; IIIa, IIIaa and IIIb; IVa, IVaa and IVb; Va, Vaa and Vb, respectively, as those formulae are defined herein. Hence, suitable and preferred substituent groups of Formulae I, Ixe2x80x3, II, IIxe2x80x3, III, IV and V are also suitable and preferred substituent groups of compounds of Formulae Ixe2x80x2, Ia, Iaa, Ib, IIa, IIaa, IIb, IIIa, IIIaa, IIIb, IVa, IVaa, IVb, Va, Vaa and Vb unless otherwise indicated.) Methyl, ethyl and propyl including isopropyl are particularly preferred alkyl groups of compounds of the invention. As used herein, the term alkyl unless otherwise modified refers to both cyclic and noncyclic groups, although of course cyclic groups will comprise at least three carbon ring members. Preferred alkenyl and alkynyl groups of compounds of the invention have one or more unsaturated linkages and from 2 to about 12 carbon atoms, more preferably 2 to about 8 carbon atoms, still more preferably 2 to about 6 carbon atoms, even more preferably 1, 2, 3 or 4 carbon atoms. The terms alkenyl and alkynyl as used herein refer to both cyclic and noncyclic groups, although straight or branched noncyclic groups are generally more preferred. Preferred alkoxy groups of compounds of Formulae I, Ixe2x80x3, II, IIxe2x80x3, III, IV, V, VI, VII, VIII or IX include groups having one or more oxygen linkages and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms, even more preferably 1, 2, 3 or 4 carbon atoms. Preferred alkylthio groups of compounds of Formulae I through IX (which includes Formulae Ixe2x80x3 and IIxe2x80x3) include those groups having one or more thioether linkages and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms. Alkylthio groups having 1, 2, 3 or 4 carbon atoms are particularly preferred. Preferred alkylsulfinyl groups of compounds of the invention include those groups having one or more sulfoxide (SO) groups and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms. Alkylsulfinyl groups having 1, 2, 3 or 4 carbon atoms are particularly preferred. Preferred alkylsulfonyl groups of compounds of the invention include those groups having one or more sulfonyl (SO2) groups and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms. Alkylsulfonyl groups having 1, 2, 3 or 4 carbon atoms are particularly preferred. Preferred aminoalkyl groups include those groups having one or more primary, secondary and/or tertiary amine groups, and from 1 to about 12 carbon atoms, more preferably 1 to about 8 carbon atoms, still more preferably 1 to about 6 carbon atoms, even more preferably 1, 2, 3 or 4 carbon atoms. Secondary and tertiary amine groups are generally more preferred than primary amine moieties. Suitable heteroaromatic groups of compounds of Formulae I, Ixe2x80x3, II, IIxe2x80x3, III, IV, V, VI, VII, VIII or IX contain one or more N, O or S atoms and include, e.g., coumarinyl including 8-coumarinyl, quinolinyl including 8-quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl and benzothiazol. Suitable heteroalicyclic groups of compounds of Formulae I, Ixe2x80x3, II, IIxe2x80x3, III, IV, V, VI, VII, VIII or IX contain one or more N, O or S atoms and include, e.g., tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholino and pyrrolindinyl groups. Suitable carbocyclic aryl groups of compounds of Formulae I, Ixe2x80x3, II, IIxe2x80x3, III, IV, V, VI, VII, VIII or IX include single and multiple ring compounds, including multiple ring compounds that contain separate and/or fused aryl groups. Typical carbocyclic aryl groups contain 1 to 3 separate or fused rings and from 6 to about 18 carbon ring atoms. Specifically preferred carbocyclic aryl groups include phenyl including substituted phenyl, such as 2-substituted phenyl, 3-substituted phenyl, 2,3-substituted phenyl, 2,5-substituted phenyl, 2,3,5-substituted and 2,4,5-substituted phenyl, including where the phenyl substituents are selected from the same group as defined above in Formulae I-V for R3; naphthyl including 1-naphthyl and 2-naphthyl; biphenyl; phenanthryl; and anthracyl. Suitable aralkyl groups of compounds of Formulae I, Ixe2x80x3, II, IIxe2x80x3, III, IV, V, VI, VII, VIII or IX include single and multiple ring compounds, including multiple ring compounds that contain separate and/or fused aryl groups. Typical aralkyl groups contain 1 to 3 separate or fused rings and from 6 to about 18 carbon ring atoms. Preferred aralkyl groups include benzyl and methylenenaphthyl (xe2x80x94CH2-naphthyl).
References herein to substituted R, R1, R2, R3, R4, Rxe2x80x3 and X groups of compounds of the invention refer to the specified moiety that may be substituted at one or more available positions by one or more suitable groups such as, e.g., halogen such as fluoro, chloro, bromo and iodo; cyano; hydroxyl; nitro; azido; alkanoyl such as a C1-6 alkanoyl group such as acyl and the like; carboxamido; alkyl groups including those groups having 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms and more preferably 1-3 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 12 carbon or from 2 to about 6 carbon atoms; alkoxy groups having those having one or more oxygen linkages and from 1 to about 12 carbon atoms or 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those moieties having one or more thioether linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; alkylsulfinyl groups including those moieties having one or more sulfinyl linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; alkylsulfonyl groups including those moieties having one or more sulfonyl linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; aminoalkyl groups such as groups having one or more N atoms and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; carbocylic aryl having 6 or more carbons, particularly phenyl (e.g. R being a substituted or unsubstituted biphenyl moiety); and aralkyl such as benzyl. Generally preferred substituents of substituted nitrogen and methylene X groups of compounds of Formulae I, II and VI include the groups from which R2 is selected in Formulae I, II and VI. More typical substituents of substituted nitrogen and methylene X groups of compounds of Formulae I, II and VI include substituted and unsubstituted alkyl, including C1-4 alkyl and halo-substituted C1-4 alkyl, particularly fluoro-substituted C1-4 alkyl such as trifluoromethyl, and in the case of a substituted methylene group, halogen and alkylthio.
It should be understood that alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl and aminoalkyl substituent groups described above include groups where a hetero atom is directly bonded to a ring system, such as a carbocyclic aryl group or a heterocyclic group, as well as groups where a hetero atom of the group is spaced from such ring system by an alkylene linkage, e.g. of 1 to about 4 carbon atoms.
Preferred carbocyclic ring substituents of compounds of Formulae I, Ixe2x80x3, II, IIxe2x80x3, III, IV, V, VI, VII, VIII or IX (including substituents of the group R where R is a carbocyclic ring such as phenyl or naphthyl, i.e. compounds of Formula Ia, Iaa, Ila, IIaa, IIIa, IIIaa, IVa, IVaa, Va and Vaa where p or sxe2x89xa71 and Rxe2x80x3 is other than hydrogen) include halogen, particularly F, Cl and Br; hydroxyl; azido; substituted or unsubstituted alkyl having 1 to about 6 carbons such as methyl, ethyl, propyl and butyl, and including halogenated alkyl, particularly fluoro-alkyl having 1 to about 6 carbon atoms; substituted and unsubstituted alkoxy having 1 to about 6 carbons and including halogenated alkoxy, particularly fluoro-alkoxy having 1 to about 6 carbon atoms; substituted and unsubstituted alkylthio having 1 to about 6 carbons; substituted and unsubstituted alkylsulfinyl having 1 to about 6 carbons; substituted and unsubstituted alkylsulfonyl having 1 to about 6 carbons; and carbocylic aryl, particularly phenyl to provide a substituted phenyl R group that is bi-phenyl. Typically preferred phenyl ring substituents have 1 to 4 carbon atoms with methyl, ethyl, propyl including isopropyl and butyl including sec-butyl being particularly preferred. Halogen-substituted alkyl and alkoxy groups are also particularly preferred including fluoroalkyl having 1, 2, 3 or 4 carbon atoms such as trifluoromethyl and fluoro-substituted alkoxy having 1, 2, 3 or 4 carbon atoms such as trifluoromethoxy (xe2x80x94OCF3). Methylthio (xe2x80x94SCH3) and ethylthio (xe2x80x94SCH2CH3) are also particularly preferred phenyl ring substituents. Preferred alkylsulfinyl ring substituents of carbocyclic aryl groups of compounds of the invention typically have one or more sulfoxide groups, more typically, one or two sulfoxide groups and from 1 to about 8 carbon atoms, more preferably 1 to about 6 carbon atoms, even more preferably 1 to about 3 carbon atoms. Methylsulfinyl (xe2x80x94S(O)CH3) and ethylsulfinyl (xe2x80x94S(O)CH2CH3) are particularly preferred R2, R3 and R4 alkylsulfinyl ring substituents as well as preferred ring substituents of a substituted carbocyclic R group. In particular, methylsulfinylphenyl and ethylsulfinylphenyl are preferred R groups. Preferred substituted alkylsulfinyl substituents include haloalkylsulfinyl groups that contain one or more F, Cl, Br or I atoms, preferably one or more F atoms, and preferably 1 to about 3 carbon atoms, more preferably one or two carbon atoms. Specifically preferred groups include fluoromethylsulfinyl, particularly trifluoromethylsulfinyl (xe2x80x94S(O)CF3), and fluoroethylsulfinyl such as 2-trifluoroethylsulfinyl (xe2x80x94S(O)CH2CF3) and pentafluoroethylsulfinyl (xe2x80x94S(O)CF2CF3). Preferred alkylsulfonyl ring substituents of carbocyclic aryl group compounds of the invention have one or more sulfono (SO2) groups, more typically one sulfono group, and from 1 to about 8 carbon atoms, still more preferably 1 to about 6 carbon atoms, even more preferably 1 to about 3 carbon atoms. Methylsulfonyl (xe2x80x94S(O)2CH3) and ethylsulfonyl (xe2x80x94S(O)2CH2CH3) are particularly preferred sulfonoalkyl ring substituents. Preferred substituted alkylsulfonyl substituents include haloalkylsulfonyl groups that contain one or more F, Cl, Br or I atoms, preferably one or more F atoms, and preferably 1 to about 3 carbon atoms, more preferably one or two carbon atoms. Specifically preferred groups include fluoromethylsulfonyl, particularly trifluoromethylsulfonyl (xe2x80x94S(O)2CF3), and fluoroethylsulfonyl such as 2-trifluoroethylsulfonyl (xe2x80x94S(O)2CH2CF3) and pentafluoroethylsulfonyl (xe2x80x94S(O)2CF2CF3).
Without wishing to be bound by theory, compounds of the invention that contain an alkylsulfinyl and/or alklsulfonyl group, may be, in effect, xe2x80x9cpro-drugsxe2x80x9d wherein after administration of the compound to a subject the sulfinyl or sulfonyl group(s) are metabolized (reduced) in vivo to the corresponding sulfide moiety.
Specifically preferred compounds of Formula I include the following:
N-(4benzyloxyphenyl)-1-indolinylcarboximidamide;
N-(4-methoxynaphthyl)-1-indolinylcarboximidamide;
N-(1-naphthyl)-1-indolinylcarboximidamide;
N-(3,4-dimethoxynaphthyl)-1-indolinylcarboximidamide;
N-(3,4-dichlorophenyl)-1-indolinylcarboximidamide;
N-(1-naphthyl)-1-(7-ethyl)-indolinylcarboximidamide;
N-(2-naphthyl)-1-(7-ethyl)-indolinylcarboximidamide;
N-(4-sec-butylphenyl)-1-indolinylcarboximidamide;
N-(2,3-dichlorophenyl)-1-indolinylcarboximidamide;
N-(2,3-dimethylphenyl)-1-indolinylcarboximidamide;
N-(5,6,7,8-tetrahydro-1-naphthyl)-1-indolinylcarboximidamide;
N-(2-biphenyl)-1-indolinylcarboximidamide;
N-(1-naphthyl)-N-methyl-1-indolinylcarboximidamide;
N-(2-naphthyl)-1-indolinylcarboximidamide;
N-phenyl-1-indolinylcarboximidamide;
N-(2-chlorophenyl)-1-indolinylcarboximidamide;
N-(2-methylphenyl)-1-indolinylcarboximidamide;
N-(3-methylphenyl)-1-indolinylcarboximidamide;
N-(2,5-dimethylphenyl)-1-indolinylcarboximidamide;
N-(2,5-dibromophenyl)-1-indolinylcarboximidamide;
N-(2,5-dichlorophenyl)-1-indolinylcarboximidamide;
N-(5-acenaphthyl)-1-(5-methoxy)-indolinylcarboximidamide;
N-(5-acenaphthyl)-1-(5-bromo)-indolinylcarboximidamide;
N-(2,3-dimethoxyphenyl)-1-indolinylcarboximidamide;
and pharmaceutically acceptable salts of said compounds.
N-(1-naphthyl)-1-indolinylcarboximidamide and pharmaceutically acceptable salts thereof are particularly preferred compounds of Formula I.
Additional preferred compounds of Formula I include the following where the compound is structurally depicted above the chemical name thereof, and pharmaceutically acceptable salts of these depicted compounds. 
Specifically preferred compounds of Formula II include the following:
N-(1-naphthyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(1-naphthyl)-1-(7-trifluoromethyl)-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(1-naphthyl)-1-(7-methyl)-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2,5-dibromophenyl)-1-(7-trifluoromethyl)-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(1-naphthyl)-1-(2-trifluoromethyl)-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(4-benzyloxyphenyl)-1-(1,2,3,4-tetrahydroquinoylinyl)carboximidamide;
N-(4-methoxynaphtyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(3,4-dichlorophenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(5-acenaphthyl)-1-(5-methoxy)-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(5-acenaphthyl)-1-(5-bromo)-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(1-naphthyl)-1-(7-ethyl)-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(4-sec-butylphenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2,3-dichlorophenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2,3-dimethylphenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(5,6,7,8-tetrahydro-1-naphthyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2-biphenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(3-biphenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(1-naphthyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2-ethylphenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(3-ethylphenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2,5-dimethylphenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2-chloro-5-ethylphenyl)-1-(7-trifluoromethyl)-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2,5-dibromophenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2,5-dichlorophenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(3-methylthiophenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2,3-dichlorophenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
N-(2,3-difluorophenyl)-1-(1,2,3,4-tetrahydroquinolinyl)carboximidamide;
and pharmaceutically acceptable salts of said compounds.
N-(2,5-dibromophenyl)-1-(7-trifluoromethyl)-(1,2,3,4-tetrahydroquinolinyl)carboximidamide and pharmaceutically acceptable salts thereof are particularly preferred compounds of Formula II, i.e. the compound of the following structure and pharmaceutically acceptable salts thereof: 
Additional preferred compounds of Formulae II and IIxe2x80x2 include the following where the compound is structurally depicted above the chemical name thereof, and pharmaceutically acceptable salts of these depicted compounds. 
Specifically preferred compounds of Formula III include the following:
N-(1-naphthyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(1-naphthyl)-1-(7-trifluoromethyl)-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(1-naphthyl)-1-(7-methyl)-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(2,5-dibromophenyl)-1-(7-trifluoromethyl)-(1,2,3,4-tetetrahydroisoquinolinyl)carboximidamide;
N-(1-naphthyl)-1-(2-trifluoromethyl)-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(4-benzyloxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(4-methoxynaphthyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboxidamide;
N-(3,4-dichlorophenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(5-acenaphthyl)-1-(5-methoxy)-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(5-acenaphthyl)-1-(5-bromo)-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(1-naphthyl)-1-(7-ethyl)-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(4sec-butylphenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(2,3-dichlorophenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(2,3-dimethylphenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(5,6,7,8-tetrahydro-1-naphthyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(2-biphenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(3-biphenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(1-naphthyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(2-ethylphenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(3-ethylphenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(2,5-dimethylphenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(2-chloro-5-ethylphenyl)-1-(7-trifluoromethyl)-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(2,5-dibromophenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(2,5-dichlorophenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(3-methylthiophenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(2,3-dichlorophenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
N-(2,3-difluorophenyl)-1-(1,2,3,4-tetrahydroisoquinolinyl)carboximidamide;
and pharmaceutically acceptable salts of said compounds.
Specifically preferred compounds of Formula IV include the following:
N-(3-biphenyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(1-naphthyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(2-methylphenyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(2,3-dimethylphenyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(2,5-dimethylphenyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(4-benzyloxyphenyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(4-methoxynaphthyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(3,4-dichlorophenyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(5-acenaphthyl)-1-(5-methoxy)-1-(benz[cd]indolinyl)carboximidamide;
N-(5-acenaphthyl)-1-(5-bromo)-(benz[cd]indolinyl)carboximidamide;
N-(1-naphthyl)-1-(7-ethyl)-(benz[cd]indolinyl)carboximidamide;
N-(4-sec-butylphenyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(2,3-dichlorophenyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(3-methylphenyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(5,6,7,8-tetrahydro-1-naphthyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(2-biphenyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(1-naphthyl)-1-(7-trifluoromethyl)-(benz[cd]indolinyl)carboximidamide;
N-(3-ethylphenyl)-1-(benz[cd]indolinyl)carboximidamide;
N-(2,5-dibromophenyl)-1-benz[cd]indolinyl)carboximidamide;
N-(2,5-dichlorophenyl)-1-(benz[cd]indolinyl)carboximidamide;
and pharmaceutically acceptable salts of said compounds.
N-(2-methylphenyl)-1-(benz[cd]indolinyl)carboximidamide is a particularly preferred compound of Formula IV.
Additional preferred compounds of Formula IV include the following where the compound is structurally depicted above the chemical name thereof, and pharmaceutically acceptable salts of these depicted compounds. 
Specifically preferred compounds of Formula V include the following:
N-(1-naphthyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(4-benzyloxyphenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(4-methoxynaphthyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(3,4dichlorophenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(5-acenaphthyl)-1-(5-methoxy)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(5-acenaphthyl)-1-(5-bromo)-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(1-naphthyl)-1-(7-ethyl)-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(4-sec-butylphenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(2,3-dichlorophenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(2,3-dimethylphenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(5,6,7,8-tetrahydro-1-naphthyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(2-biphenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(3-biphenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(1-naphthyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(1-naphthyl)-1-(7-trifluoromethyl)-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(2-methylphenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(3-ethylphenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(2,5-dimethylphenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
N-(2-ethylphenyl)-1-(5,6-dihydrophenanthridinyl)carboximidamide;
and pharmaceutically acceptable salts of said compounds.
Specifically preferred compounds of Formula VI include the following where the where the compound is structurally depicted above the chemical name thereof, and pharmaceutically acceptable salts of these depicted compounds: 
Specifically preferred compounds of Formula VII include the following where the where the compound is structurally depicted above the chemical name thereof, and pharmaceutically acceptable salts of these depicted compounds: 
Specifically preferred compounds of Formulae VIII and IX include the following where the where the compound is structurally depicted above the chemical name thereof, and pharmaceutically acceptable salts of these depicted compounds: 
Excluded from certain aspects of the invention are N-(alkylphenyl)-1-indolinylcarboximidamide compounds (i.e. compounds of Formula I where X is CH2 and R is alkyl-substituted phenyl, particularly where R1 is H), specifically N-(mono-alkylphenyl)-1-indolinylcarboximidamide such as N-(m-ethylphenyl)-1-indolinyl carboximidamide; as well as compounds of the invention where R is acenaphthyl, particularly where R is unsubstituted acenaphthyl and/or ring substituents R2 and R3 are each only hydrogen, and/or where X is CH2 in the case of Formulae I and II, and/or one of R and R1 is hydrogen; as well as compounds of Formula III where R or R1 is aralkyl, particularly where ring substituents R2 and R3 are each only hydrogen, and/or R and R1 are each other than hydrogen.
Compounds of the invention can be prepared by the reaction of a suitable precursor compound, e.g. indolinyl (or derivative thereof) compound, 1,2,3,4-tetrahydroquinolinyl (or derivative thereof) compound, 1,2,3,4-tetrahydroisoquinolinyl compound, benz[cd]indolinyl compound, 5,6-dihydrophenanthridinyl compound, 2,3,4,5-tetrahydro-[1,5]-benzothiazepine compounds (or deriviative thereof, e.g. where X is other atom), 2a,3,4,5-tetrabenz[cd]indoline compound, 5,6,11,12-tetrahydrodiben[b,f]azocine compound, etc. (depending on whether a compound of Formulae I, Ixe2x80x3, II, IIxe2x80x3, III, IV, V, VI, VII, VIII or IX respectively, is being prepared) with a preformed alkyl or aryl cyanamide (see S. R. Safer, et al., J. Org. Chem., 13:924 (1948)) or the corresponding N-substituted alkyl or aryl cyanamide. Typically, a salt of the amine (e.g. an HCl salt) is reacted with the cyanamide.
More particularly, compounds the invention can be suitably prepared by reaction of an appropriate indolinyl (or derivative thereof) salt (to prepare compounds of Formulae I, Ixe2x80x2, Ixe2x80x3, Ia, Iaa or Ib), 1,2,3,4-tetrahydroquinolinyl (or derivative thereof) salt (to prepare compounds of Formulae II, IIxe2x80x3, IIa, IIaa or IIb), 1,2,3,4-tetrahydroisoquinolinyl salt (to prepare compounds of Formulae III, IIIa, IIIaa or IIIb), benz[cd]indolinyl salt (to prepare compounds of Formulae IV, IVa, IVaa or IVb), or 5,6-dihydrophenanthridinyl salt (to prepare compounds of Formulae V, Va, Vaa or Vb) or other appropriate salt such as salts of above mentioned precursor compounds (to form compounds of Formulae VI-IX) with a substituted cyanamide in a suitable solvent such as toluene, chlorobenzene or the like under an inert atmosphere such as argon or nitrogen as exemplified in the Scheme below. The reaction solution is then heated e.g. from about 110xc2x0 to 120xc2x0 C. for 2 to about 16 hours until reaction completion, e.g. as indicated by thin layer chromatography. The reaction solution is then cooled to room temperature, and the solvent is then removed under reduced pressure to provide the desired compound of the invention. The crude product then can be purified by recrystallization and/or column chromatography, e.g. by elution one or more times on silica gel (e.g., 60-200 mesh, 50xc3x97 w/w) with suitable solvents. See Example 2 which follows for exemplary conditions.
The indolinyl (or derivative thereof), 1,2,3,4-tetrahydroquinoline (or derivative thereof), 1,2,3,4-tetrahydroisoquinoline, benz[cd]indolinyl or 5,6-dihydrophenanthridinyl to other presursor such as those mentioned above (for Formulae VI-IX) and cyanamide reagents with appropriate substituents are commercially available or can be readily prepared by known procedures. For example, the cyanamide starting material can be synthesized from the correspondingly substituted amine by treatment with cyanogen bromide (BrCN) in a suitable solvent such as dry ethyl ether or toluene at reduced temperatures (e.g. 0xc2x0 C.) or room temperature. As exemplified in the Scheme below, the amine to be reacted with cyanogen bromide is substituted with the R moiety as defined above for Formulae I, Ixe2x80x3, II, IIxe2x80x3, III, IV, V, VI, VII, VIII or IX (in the Scheme, that R moiety is exemplified as phenyl which may be ring-substituted by groups R1 and R2). Thus, various R groups of compounds of Formula I through IX (Which includes Formulae Ixe2x80x3 and IIxe2x80x3) can be provided by use of suitable substituted amines that are reacted with BrCN, such as e.g. substituted and unsubstituted anilines as shown in the Scheme, substituted and unsubstituted 1-naphthylamine, 2-naphthylamine, acenaphthylamine, etc. R1 groups other than hydrogen of compounds of Formulae I through IX can be readily provided by reaction of a substituted cyanamide with a suitable nucleophile such as a halide reagent (e.g., a substituted or unsubstituted alkyl or alkenyl iodide or bromide). Thus, as exemplified in the Scheme below, the aryl cyanamide is reacted with NaH in a solvent of tetrahydrofuran and reacted with the iodide reagent R1xe2x80x94I, such as substituted or unsubstituted methyl, ethyl, propyl, butyl, etc. iodide, an alkenyl iodide, etc. Also, compounds of the invention having an R1 group of methyl can be prepared by reaction of a mono-substituted amine (e.g., an aniline, naphthylamine or acenaphthylamine) with formic acid followed by treatment with lithium aluminum hydride to provide the corresponding methyl-substituted cyanamide (e.g., C6H5N(CH3)CN from unsubstituted aniline). Alkylsulfinyl-substituted or alkylsulfonyl-substituted reagents, that can provide correspondingly substituted compounds of the invention as described above, can be provided by oxidation (e.g., H2O2) of alkylthio-substituted reagents. See for instance Example 46 which follows.
While the Scheme depicts preparation of compounds of Formula I, the same procedures can be employed to prepare compounds of Formulae Ixe2x80x2, II, IIxe2x80x3, III, IV, V, VI, VII, VIII or IX by use of a 1,2,3,4-tetrahydroquinolinyl (or derivative thereof) salt, 1,2,3,4-tetrahydroisoquinolinyl salt, benz[cd]indolinyl salt or 5,6-dihydrophenanthridinyl salt or other corresponding salt for compounds of Formulae VI through IX, respectively, in place of the indolinyl salt shown in the Scheme. 
Compounds of Formula II where R and R1 are each hydrogen can be prepared by reaction of 1,2,3,4-tetrahydroquinoline compound with cyanamide. R2 substituents can be provided by reaction of a substituted or unsubstituted quinoline compound with a Grignard reagent followed by hydrogenation to provide the substituted 1,2,3,4-tetrahydroquinoline compound. See Example 3 which follows for an exemplary procedure. See also Examples 41 and 42 which follow. Compounds of Formulae Ixe2x80x3, IIxe2x80x3 and VI where X is xe2x80x94S(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94 can be prepared by oxidation (e.g. with H2O2 and/or with sodium periodate) of the corresponding preformed compounds where the ring member X is xe2x80x94Sxe2x80x94. See for instance Example 47 which follows.
The amine starting materials are commercially available and/or can be readily prepared. For example, benz[cd]indoline and 5,6-dihydrophenanthridine reagents can be prepared treatment of a benz[cd]indo-2(1H)-one compound or 5,6-dihydrophenanthridinone compound with a base such as diborane in a suitable solvent such as tetrahydrofuran. See Example 1 which follows for exemplary conditions. Chiral compounds of the invention may be used as optically enriched or racemic mixtures. An optically enriched mixture contains substantially more (e.g. about 60%, 70%, 80% or 90% or more) of one enantiomer or diastereoisomer than the other stereoisomers. Optically enriched mixtures can be obtained by known procedures, e.g., column chromatography using an optically active binding material or formation of a salt using an optically active material, particularly an optically active acid. Particularly preferred optically enriched mixtures include sulfinyl-containing compound of the invention. e.g. compounds of Formulae Ixe2x80x3, IIxe2x80x3 or VI where X is xe2x80x94S(O)xe2x80x94, or compounds having having an alkylsulfinyl or other sulfinyl substituent. Such optically active mixtures of sulfinyl-containing compounds can be readily prepared. e.g. by column chromatography using an optically active binding material.
As discussed above, the present invention includes methods for treating preventing certain neurological disorders, including the consequences of stroke, heart attack and traumatic head or brain injury, epilepsy or neurodegenerative diseases comprising the administration of an effective amount of one or more compounds of the invention to a subject including a mammal, particularly a human, in need of such treatment. In particular, the invention provides methods for treatment and/or prophylaxis of nerve cell death (degeneration) resulting e.g. from hypoxia, hypoglycemia, brain or spinal cord ischemia, brain or spinal cord trauma, stroke, heart attack or drowning. Typical candidates for treatment include e.g. heart attack, stroke and/or persons suffering from cardiac arrest neurological deficits, brain or spinal cord injury patients, patients undergoing major surgery such as heart surgery where brain ischemia is a potential complication and patients such as divers suffering from decompression sickness due to gas emboli in the blood stream. Candidates for treatment also will include those patients undergoing a surgical procedure involving extra-corporal circulation such as e.g. a bypass procedure.
The invention in particular provides methods for treatment which comprise administration of one or more compounds of the invention to a patient that is undergoing surgery or other procedure where brain or spinal cord ischemia is a potential risk. For example, carotid endarterectomy is a surgical procedure employed to correct atherosclerosis of the carotid arteries. Major risks associated with the procedure include intraoperative embolization and the danger of hypertension in the brain following increased cerebral blood flow, which may result in aneurism or hemorrhage. Thus, an effective amount of one or more compounds of the present invention could be administered pre-operatively or peri-operatively to reduce such risks associated with carotid endarterectomy, or other post-surgical neuorological deficits.
The invention further includes methods for prophylaxis against neurological deficits resulting from e.g. coronary artery bypass graft surgery and aortic valve replacement surgery, or other procedure involving extra-corporal circulation. Those methods will comprise administering to a patient undergoing such surgical procedures an effective amount of one or more compounds of the invention, typically either pre-operatively or peri-operatively.
The invention also provides methods for prophylaxis and treatment against neurological injury for patients undergoing myocardial infarction, a procedure that can result in ischemic insult to the patient. Such methods will comprise administering to a patient undergoing such surgical procedure an effective amount of one or more compounds of the invention, typically either pre-operatively or peri-operatively.
Also provided are methods for treating or preventing neuropathic pain such as may experienced by cancer patients, persons having diabetes, amputees and other persons who may experience neuropathic pain. These methods for treatment comprise administration of an effective amount of one or more compounds of the invention to a patient in need of such treatment.
The invention also provides methods for treatment and prophylaxis against retinal ischemia or degeneration and resulting visual loss. For example, a compound of the invention can be administered parenterally or by other procedure as described herein to a subject a suffering from or susceptible to ischemic insult that may adversely affect retinal function, e.g., significantly elevated intraocular pressures, diseases such as retinal artery or vein occlusion, diabetes or other ischemic ocular-related diseases. Post-ischemic administration also may limit retinal damage. The invention also includes methods for treating and prophylaxis against decreased blood flow or nutrient supply to retinal tissue or optic nerve, or treatment or prophylaxis against retinal trauma or optic nerve injury. Subjects for treatment according to such therapeutic methods of the invention may be suffering or susceptible to retinal ischemia that is associated with atherosclerosis, venous capillary insufficiency, obstructive arterial or venous retinopthies, senile macular degeneration, cycstoid macular edema or glaucoma, or the retinal ischemia may be associated with a tumor or injury to the mammnal. Intravitreal injection of a compound of the invention also may be a preferred administration route to provide more direct treatment to the ischemic retina.
The invention also provides methods for treatment of a subject suffering from shingles as well as treatment of a person suffering from or susceptible to migraines, particularly to alleviate the pain and discomfort associated with those disorders. These methods comprise administration of an effective amount of one or more compounds of the invention to a patient in need of treatment.
The invention further provides a method of treating Korsakoff""s disease, a chronic alcoholism-induced condition, comprising administering to a subject including a mammal, particularly a human, one or more compounds of the invention in an amount effective to treat the disease. Compounds of the invention are anticipated to have utility for the attenuation of cell loss, hemorrhages and/or amino acid changes associated with Korsakoff""s disease.
As discussed above, the invention also includes methods for treating a person suffering from or susceptible to cerebral palsy, emesis, narcotic withdrawal symptoms and age-dependent dementia, comprising administering to a subject including a mammal, particularly a human, one or more compounds of the invention in an amount effective to treat the condition.
As discussed above, preferred compounds of the invention in a standard anticonvulsant in vivo audiogenic test, such as the audiogenic mouse assay of Example 48 which follows, where DBA/2 mice about 20-23 days old are injected intraperitoneally with a test compound 30 minutes prior to being placed in a bell jar with exposure to auditory stimulus of 12 KHz sine wave at 110-120 db. References herein in vivo xe2x80x9caudiogenic assayxe2x80x9d are intended to refer to that protocol. Generally preferred compounds exhibit 20% or more inhibition (relative to subjects treated with vehicle control only) at a dose of 20 mg/kg, more preferably about 50% or more or 70% or more inhibition at a dose of 20 mg/kg in such an in vivo audiogenic assay. As discussed above, activity in the audiogenic assay has been recognized as indicative that a test compound has neuroprotective properties. See, e.g., M. Tricklebank et al., European Journal of Pharmacology, supra; T. Seyfried, Federation Proceedings, supra.
The invention also provides methods for determining binding activity of compounds of the invention as well as in vitro and in vivo binding activity diagnostic methods using one or more radiolabelled compounds of the invention, e.g., a compound of the invention that is labeled with 125I, tritium, 32P, 99Tc, or the like, preferably 125I. For instance, a compound of the invention having a phenyl or other aryl substituent that is ring substituted with one or more 125I groups can be administered to a mammal and the subject then scanned for binding of the compound. Specifically, single photon emission computed tomography (xe2x80x9cSPECTxe2x80x9d) can be employed to detect such binding. Such an analysis of the mammal could e.g. aid in the diagnosis and treatment of acute cerebral ischemia. That is, a labeled compound of the invention will selectively bind to ischemic tissue of e.g. a subject""s brain to differentiate between ischemic and non-ischemic tissue and thereby assess trauma or other injury to the brain.
Accordingly, the invention includes compounds of the invention that contain a radiolabel such as 125I, tritium, 32P, 99Tc, or the like, preferably 125I. Such radiolabelled compounds can be suitably prepared by procedures known in the synthesis art. For example, a compound of the invention having an aromatic group, such as phenyl, that has a bromo or chloro ring substituent can be employed in an exchange labeling reaction to provide the corresponding compound having an 125I ring substituent.
Compounds of the invention may be used in therapy in conjunction with other medicaments. For example, for treatment of a stroke victim or a person susceptible to stroke, one or more compounds of Formulae I, II, III, IV or V, or one or compounds of Formulae Ixe2x80x3, IIxe2x80x3, VI, VII, VIII or IX, may be suitably administered together with a pharmaceutical targeted for interaction in the blood clotting mechanism such as streptokinase, tPA, urokinase and other agents that lyse clots. Also, one or more compounds of the invention may be administered together with agents such as heparin and related heparin-based compounds, acenocoumarol or other known anticoagulants.
The compounds of this invention can be administered intranasally, orally or by injection, e.g., intramuscular, intraperitoneal, subcutaneous or intravenous injection, or by transdermal, intraocular or enteral means. The optimal dose can be determined by conventional means. Compounds of the present invention are suitably administered to a subject in the protonated and water-soluble form, e.g., as a pharmaceutically acceptable salt of an organic or inorganic acid, e.g., hydrochloride, sulfate, hemi-sulfate, phosphate, nitrate, acetate, oxalate, citrate, maleate, mesylate, etc.
Compounds of the invention can be employed, either alone or in combination with one or more other therapeutic agents as discussed above, as a pharmaceutical composition in mixture with conventional excipient, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, enteral or intranasal application which do not deleteriously react with the active compounds and are not deleterious to the recipient thereof. Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, etc. The pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously react with the active compounds.
For parenteral application, particularly suitable are solutions, preferably oily or aqueous solutions as well as suspensions, emulsions, or implants, including suppositories. Ampules are convenient unit dosages.
For enteral application, particularly suitable are tablets, dragees or capsules having talc and/or carbohydrate carrier binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch. A syrup, elixir or the like can be used wherein a sweetened vehicle is employed. Sustained release compositions can be formulated including those wherein the active component is protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, etc.
Intravenous or parenteral administration, e.g., sub-cutaneous, intraperitoneal or intramuscular administration are preferred. The compounds of this invention are particularly valuable in the treatment of mammalian subjects, e.g., humans, to provide neuroprotective therapy and/or prophylaxis. Typically, such subjects include those afflicted with neurodegenerative diseases such as Parkinson""s disease, Huntington""s disease, Amyotrophic Lateral Sclerosis, Alzheimer""s disease, Down""s Syndrome and Korsakoff""s disease. Also suitable for treatment are those subjects suffering from or likely to suffer from nervous system dysfunctions resulting from, for example, epilepsy or nerve cell degeneration which is the result of hypoxia, hypoglycemia, brain or spinal chord ischemia or brain or spinal chord trauma. As discussed above, typical candidates for treatment include heart attack, stroke, brain or spinal cord injury patients, patients undergoing major surgery where brain or spinal cord ischemia is a potential complication and patients such as divers suffering from decompression sickness due to gas emboli in the blood stream.
It will be appreciated that the actual preferred amounts of active compounds used in a given therapy will vary according to the specific compound being utilized, the particular compositions formulated, the mode of application, the particular site of administration, etc. Optimal administration rates for a given protocol of administration can be readily ascertained by those skilled in the art using conventional dosage determination tests conducted with regard to the foregoing guidelines. In general, a suitable effective dose of one or more compounds of Formulae I, II, III, IV or V, or one or compounds of Formulae Ixe2x80x3, IIxe2x80x3, VI, VII, VIII or IX, particularly when using the more potent compound(s) of Formulae I, II, III, IV or V, or one or compounds of Formulae Ixe2x80x3, IIxe2x80x3, VI, VII, VIII or IX, will be in the range of from 0.01 to 100 milligrams per kilogram of bodyweight of recipient per day, preferably in the range of from 0.01 to 20 milligrams per kilogram bodyweight of recipient per day, more preferably in the range of 0.05 to 4 milligrams per kilogram bodyweight of recipient per day. The desired dose is suitably administered once daily, or several sub-doses, e.g. 2 to 4 sub-doses, are administered at appropriate intervals through the day, or other appropriate schedule. Such sub-doses may be administered as unit dosage forms, e.g., containing from 0.05 to 10 milligrams of compound(s) of Formulae I, II, III, IV or V, or one or compounds of Formulae Ixe2x80x3, IIxe2x80x3, VI, VII, VIII or IX, per unit dosage, preferably from 0.2 to 2 milligrams per unit dosage.
Compounds of the invention also should be useful as rubber accelerators. See U.S. Pat. No. 1,411,713 for a discussion of rubber accelerator applications.
The entire text of all documents cited herein are incorporated by reference herein. The following non-limiting examples are illustrative of the invention.
General Comments
In the following examples, all percentages reported herein, unless otherwise specified, are percent by weight. All temperatures are expressed in degrees Celsius.
Melting points were determined in open capillary tubes on a Thomas-Hoover apparatus and are uncorrected. Thin-layer chromatography was performed on Baker-flex 1B2-F silica gel plates. Compounds were visualized on TLC with 254-nM UV light or as a blue spot with bromcresol spray reagent (Sigma Chemical Co.). Preparative TLC was performed on Analtech GF precoated silica gel (1000 xcexcm) glass-backed plates (20xc3x9720 cm). The IR, 1H and 13C NMR spectra of all compounds were consistent with their assigned structures. NMR spectra were recorded on Varian Gemini 300 and the chemical shifts were reported in ppm (xcex4) relative to the residual signal of the deuterated solvent (CDCl3, xcex47.26; CHD2OD, xcex43.30). Elemental analyses were performed by either Galbraith Laboratories (Knoxville, Tenn.) or MHW Laboratories (Tuscon, Ariz.). High Resolution Mass spectra (HRMS) were recorded on a Finnegan MAT 90. HPLC were performed on a C18 reverse phase column using 50:50 water:acetonitrile with 0.1% TFA as a mobile phase. BrCN was obtained from Aldrich Chemical Co., and was used as received. All starting amines were obtained from commercial sources and were purified by standard procedures before use, or they were prepared by published procedures. Chlorobenzene, ether (Et2O) and tetrahydrofuran (THF) were anhydrous quality solvents (Sure Seal) supplied by Aldrich. All other solvents were reagent grade. Alkyl- and arylcyanamides were prepared as described above and according to published procedures (e.g., PCT/US92/01050) by reaction of the amines with BrCN in ether.